The coming NHGRI Centers for Common Disease Genomics (CCDG) and Centers for Mendelian Genomics (CMG) plan to generate whole genome sequencing (WGS) data on over 200,000 individuals. WGS will provide comprehensive and complete genetic data across coding and non-coding variation, presenting an unprecedented opportunity for discovery in the genetic analysis of human diseases. However, a lack of powerful analytic tools that fully realize the potential of these data has emerged as a bottleneck for effectively translating rich information contained in these massive WGS data into meaningful insights about human diseases. There is a pressing need to develop powerful and robust analytic methods for WGS that can accelerate genetic discoveries. To meet this need, we have assembled an interdisciplinary team of computational biologists, geneticists, and statisticians. Building on our extensive track record in sequencing studies, statistical genetics, functional analysis and computational biology, we will power the next round of genetic discoveries by (1) building a massive WGS control sample and developing the methods for incorporating these controls in studies of complex and Mendelian diseases; (2) creating more powerful statistical methods for rare variant analysis through the incorporation of functional and regulatory information and advanced statistical tools; (3) establishing methods to analyze multiple phenotypes to boost the power for association and understand how different phenotypes relate genetically. These methods will enhance our ability to identify novel associations across a wide range of genetic architectures, from Mendelian diseases driven by a strong acting allele to complex polygenic traits. Novel associations promise to lay the foundation for gaining new insight into the biological mechanisms driving disease and be the bedrock for precision prevention and medicine strategies. We will collaborate with the investigators of the Genome Sequencing Program, and will share the developed data resources, tools and methods with the community through user-friendly open source software and educational modules.